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Background:  Previous genome-wide association studies revealed that the chromosome 9p21.3 locus is associated with an increased risk of myocardial infarction (MI) and diabetes mellitus (DM). However, it is unclear whether the 9p21.3-MI association is direct or mediated by pathways related to DM.   Study Design:  We applied mediation analysis to examine the potential mediating effect of DM on the association between the 9p21.3 genetic risk score (GRS; ranged from 0 to 8) and MI in a case-control study of 865 MI patients and 927 controls without coronary artery disease (CAD). The GRS combining 4 lead 9p21.3 single nucleotide polymorphisms (rs1333040, rs4987574, rs2383207, and rs1333049) was constructed.   Results:  Each 1 unit increase in weighted 9p21.3 GRS was associated with a 9% increased DM risk (95% confidence interval (CI) 1.00, 1.19) in the control group and a 14% increased MI risk (95% CI 1.09, 1.20). Mediation analyses yielded a direct-effect odds ratio (OR) of 1.06 (95% CI 1.04, 1.08) and an indirect-effect OR of 1.00 (95% CI 0.99, 1.01) for weighted GRS. DM mediated 4.40% (95% CI 3.42, 6.52) of the total association between the weighted GRS and MI risk. Individuals with the highest quartile of 9p21.3 GRS and DM had a 6-fold higher MI risk than those with the lowest quartile of 9p21.3 GRS and non-DM (OR 6.03, 95% CI 3.48, 10.5).   Conclusion:  DM is a weak mediator that explains a small fraction of the 9p21. 3-MI association in Chinese adults. Nevertheless, there is a strong synergistic effect between DM and the 9p21.3 GRS on MI risk.

frontiers in endocrinology

Mediating Effect of Diabetes Mellitus on the Association Between Chromosome 9p21.3 Locus and Myocardial Infarction Risk: A Case-Control Study in Shanghai, China